Crystalline forms

ABSTRACT

The invention relates to crystalline forms of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbony]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride, processes for the preparation thereof, pharmaceutical compositions comprising said crystalline forms, pharmaceutical compositions prepared from such crystalline forms and their use as a medicament, especially as a P2Y12 receptor antagonist.

The invention relates to novel crystalline forms of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionylypiperazine-1-carboxylicacid butyl ester hydrochloride (hereinafter also referred to as“COMPOUND⋅HCl”), processes for the preparation thereof, pharmaceuticalcompositions comprising said crystalline forms, pharmaceuticalcompositions comprising4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester (hereinafter also referred to as “COMPOUND”) whereinCOMPOUND is obtained from said crystalline forms of COMPOUND⋅HCl,pharmaceutical compositions prepared from such crystalline forms ofCOMPOUND⋅HCl, use of the crystalline forms of COMPOUND⋅HCl as P2Y₁₂receptor antagonists in the treatment of various P2Y₁₂ receptor-mediateddiseases and disorders and use of COMPOUND as P2Y₁₂ receptor antagonistin the treatment of various P2Y₁₂ receptor-mediated diseases anddisorders wherein COMPOUND is obtained from said crystalline forms ofCOMPOUND⋅HCl.

BACKGROUND OF THE INVENTION

The circulation of blood from and to organs guarantees the supply ofoxygen, nutrients, as well as the disposal of catabolic products.Therefore, the integrity of blood vessels is essential at all times.When the vascular integrity is compromised, a highly efficient repairmechanism is activated at the site of injury resulting in the formationof a repair seal to prevent further blood loss. This fundamentalbiological process is defined as hemostasis. Thrombosis is the result ofa pathological deviation of one or several components involved inhemostasis leading to uncontrolled platelet thrombus formation andvessel occlusion. Platelets have been described to contribute tohemostasis and thrombosis since their discovery (Coller B S, Historicalperspective and future directions in platelet research. J ThrombHaemost. 2011; 9 Suppl 1:374-395). More recently, atheroscleroticlesions in combination with occlusive platelet thrombi have been foundin patients with ischemic cardiac death (Davies M J et al.,Intramyocardial platelet aggregation in patients with unstable anginasuffering sudden ischemic cardiac death. Circulation. 1986; 73:418-427).Inhibition of platelet aggregation is recognized as an effectivestrategy for the prevention of thrombosis in patients withatherosclerotic disease in the coronary (Jneid H et al., 2012 accf/ahafocused update of the guideline for the management of patients withunstable angina/non-st-elevation myocardial infarction (updating the2007 guideline and replacing the 2011 focused update): A report of theamerican college of cardiology foundation/american heart associationtask force on practice guidelines. J Am Coll Cardiol. 2012; 60:645-681;O'Gara P T et al., 2013 accf/aha guideline for the management ofst-elevation myocardial infarction: A report of the american college ofcardiology foundation/american heart association task force on practiceguidelines. Circulation. 2013; 127:e362-425), peripheral (Jagroop I A etal., The effect of clopidogrel, aspirin and both antiplatelet drugs onplatelet function in patients with peripheral arterial disease.Platelets. 2004; 15:117-125; Matsagas M et al., The effect of a loadingdose (300 mg) of clopidogrel on platelet function in patients withperipheral arterial disease. Clin Appl Thromb Hemost. 2003; 9:115-120),and cerebrovascular circulation (Liu F et al., P2Y₁₂ receptor inhibitorsfor secondary prevention of ischemic stroke. Expert Opin Pharmacother.2015; 16:1149-1165). Inhibition of P2Y₁₂ as an antiplatelet approach wasvalidated in multiple clinical studies. Several P2Y₁₂ antagonists havebeen demonstrated to effectively reduce the risk of adversecardiovascular events in patients with acute coronary syndromes (ACS)and patients undergoing percutaneous coronary intervention (PCI)(Cattaneo M, The platelet P2Y₁₂ receptor for adenosine diphosphate:Congenital and drug-induced defects. Blood. 2011; 117:2102-2112; ThomasM R et al., The future of P2Y₁₂ receptor antagonists. Platelets. 2015;26:392-398; Wiviott S D et al., Clinical evidence for oral antiplatelettherapy in acute coronary syndromes. Lancet. 2015; 386:292-302;Wallentin L, P2Y₁₂ inhibitors: Differences in properties and mechanismsof action and potential consequences for clinical use. Eur Heart J.2009; 30:1964-1977). In current treatment guidelines, P2Y₁₂ antagonistsdefine the cornerstone therapy for patients with ACS (Jneid H et al.,2012 accf/aha focused update of the guideline for the management ofpatients with unstable angina/non-st-elevation myocardial infarction(updating the 2007 guideline and replacing the 2011 focused update): Areport of the american college of cardiology foundation/american heartassociation task force on practice guidelines. J Am Coll Cardiol. 2012;60:645-681; O'Gara PT et al., 2013 accf/aha guideline for the managementof st-elevation myocardial infarction: A report of the american collegeof cardiology foundation/american heart association task force onpractice guidelines. Circulation. 2013; 127:e362-425).

Three indirect P2Y₁₂ antagonists of the thienopyridine family, whichblock the ADP-induced platelet activation and aggregation, have reachedthe market: the orally active ticlopidine, clopidogrel and prasugrel. Inaddition, two direct P2Y₁₂ antagonists, which do not require metabolicactivation and therefore display faster on- and offset of action, havereceived market approval: the nucleotide analogues ticagrelor andcangrelor.

4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester is a potent, reversible, and selective P2Y₁₂ receptorantagonist (Caroff E et al., J. Med. Chem. 2015; 58:9133-9153; WO2009/069100). Its hydrochloride salt was used as a powder in afirst-in-man clinical trial (Baldoni et al., Clinical Drug Investigation2014; 34:807-818).

Despite the fact that many attempts failed to crystallize COMPOUND⋅HClfrom several solvents in a mono-phase solvent system, it surprisinglyhas been found that a crystallization took place in certainheterogeneous solvent systems. The obtained crystalline forms ofCOMPOUND⋅HCl may have advantageous properties in view of the potentialuse of COMPOUND⋅HCl or COMPOUND as active pharmaceutical ingredient.Such advantages may include higher purity; better storage stability;better flow properties; less hygroscopicity; better reproducibility inmanufacturing (for example better filtration parameters, betterreproducibility of formation, and/or better sedimentation); and/ordefined morphology. Such crystalline forms of COMPOUND⋅HCl may beparticularly suitable in a process of manufacturing certainpharmaceutical compositions.

DESCRIPTION OF THE FIGURES

FIG. 1 shows the X-ray powder diffraction diagram of COMPOUND⋅HCl in thecrystalline form 1, wherein the X-ray powder diffraction diagram isdisplayed against Cu Kα radiation. The X-ray diffraction diagram showspeaks having a relative intensity, as compared to the most intense peakin the diagram, of the following percentages (relative peak intensitiesgiven in parenthesis) at the indicated angles of refraction 2theta(selected peaks from the range 3-30° 2theta with relative intensitylarger or equal than 10% are reported): 4.0° (100%), 5.0 (60%), 5.9°(23%), 11.7° (10%), 15.3° (13%), 19.3° (15%), 19.7° (11%), and 20.7°(10%).

FIG. 2 shows the X-ray powder diffraction diagram of COMPOUND⋅HCl in thecrystalline form 2, wherein the X-ray powder diffraction diagram isdisplayed against Cu Kα radiation. The X-ray diffraction diagram showspeaks having a relative intensity, as compared to the most intense peakin the diagram, of the following percentages (relative peak intensitiesgiven in parenthesis) at the indicated angles of refraction 2theta(selected peaks from the range 3-30° 2theta with relative intensitylarger or equal than 10% are reported): 5.2° (100%), 6.8° (26%), 8.0°(14%), 10.3° (66%), 10.8° (66%), 12.7° (10%), 15.4° (18%), 16.2° (13%),20.3° (40%), 20.5° (28%), and 21.7° (13%).

FIG. 3 shows the X-ray powder diffraction diagram of COMPOUND⋅HCl in thecrystalline form 3, wherein the X-ray powder diffraction diagram isdisplayed against Cu Kα radiation. The X-ray diffraction diagram showspeaks having a relative intensity, as compared to the most intense peakin the diagram, of the following percentages (relative peak intensitiesgiven in parenthesis) at the indicated angles of refraction 2theta(selected peaks from the range 8-30° 2theta with relative intensitylarger or equal than 10% are reported): 5.5° (100%), 7.2 (43%), 11.0°(51%), 11.5° (45%), 13.0° (10%), 14.4° (15%), 16.6° (51%), 18.1° (39%),18.5° (27%), 21.1° (32%), 22.0° (37%), 23.1° (17%), 24.3° (16%) and26.1° (10%).

In the X-ray diffraction diagrams of FIG. 1 to FIG. 3 the angle ofrefraction 2theta (20) is plotted on the horizontal axis and the countson the vertical axis.

For avoidance of any doubt, the above-listed peaks describe theexperimental results of the X-ray powder diffraction shown in FIGS. 1 to3. It is understood that, in contrast to the above peak list, only aselection of characteristic peaks is required to fully and unambiguouslycharacterize COMPOUND⋅HCl in the respective crystalline form of thepresent invention.

FIG. 4 shows the gravimetric vapour sorption behaviour in the range of20 to 75% RH at 25° C. (coming from low % RH and going to high % RH,i.e., sorption cycle) of COMPOUND⋅HCl in the crystalline form 1 asobtained from Example 1A.

FIG. 5 shows the gravimetric vapour sorption behaviour in the range of20 to 75% RH at 25° C. (coming from high % RH and going to low % RH,i.e., desorption cycle) of COMPOUND⋅HCl in the crystalline form 2 asobtained from Example 2.

FIG. 6 shows the gravimetric vapour sorption behaviour in the range of20 to 75% RH at 25° C. (coming from low % RH and going to high % RH,i.e., sorption cycle) of COMPOUND⋅HCl in the crystalline form 3 asobtained from Example 3A.

In the gravimetric vapour sorption diagrams of FIGS. 4, 5, and 6 therelative humidity (% RH) is plotted on the horizontal axis and the masschange (% dm, dry basis) on the vertical axis.

DETAILED DESCRIPTION OF THE INVENTION

1) A first embodiment of the invention relates to crystalline forms of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride (COMPOUND⋅HCl), characterized by:

-   -   a. the presence of peaks in the X-ray powder diffraction diagram        at the following angles of refraction 2θ: 4.0°, 5.0°, and 15.3°        (form 1); or    -   b. the presence of peaks in the X-ray powder diffraction diagram        at the following angles of refraction 2θ: 5.2°, 6.8°, and 10.3°        (form 2); or    -   c. the presence of peaks in the X-ray powder diffraction diagram        at the following angles of refraction 2θ: 5.5°, 11.0°, and 16.6°        (form 3).

It is understood, that the crystalline forms according to embodiment 1)comprise COMPOUND⋅HCl in form of the hydrochloric acid (hydrochloride)salt. Furthermore, said crystalline form may comprise non-coordinatedand/or coordinated solvent (especially non-coordinated and/orcoordinated water). Coordinated solvent (especially coordinated water)is used herein as term for a crystalline solvate (especially acrystalline hydrate). For the avoidance of doubt, in this applicationthe term “crystalline hydrate” encompasses non-stoichiometric hydrates.Likewise, non-coordinated solvent is used herein as term forphysiosorbed or physically entrapped solvent (definitions according toPolymorphism in the Pharmaceutical Industry (Ed. R. Hilfiker, VCH,2006), Chapter 8: U. J. Griesser: The Importance of Solvates). It isfurther understood, that the crystalline form may contain differentamounts of coordinated water as a function of relative humidity and thatthe X-ray powder diffraction diagram may thus vary with relativehumidity. Crystalline form 1 in particular comprises about 0 to 3% ofcoordinated and/or non-coordinated water. Cystalline form 2 inparticular comprises about 5 to 10% of coordinated and/ornon-coordinated water. Crystalline form 3 in particular comprises about2.5 to 8% of coordinated and/or non-coordinated water.

2) Another embodiment relates to crystalline forms of COMPOUND⋅HClaccording to embodiment 1), characterized by

-   -   a. the presence of peaks in the X-ray powder diffraction diagram        at the following angles of refraction 2θ: 4.0°, 5.0°, 11.7°,        15.3°, and 19.3° (form 1); or    -   b. the presence of peaks in the X-ray powder diffraction diagram        at the following angles of refraction 2θ: 5.2°, 6.8°, 10.3°,        10.8°, and 15.4° (form 2); or    -   c. the presence of peaks in the X-ray powder diffraction diagram        at the following angles of refraction 2θ: 5.5°, 7.2°, 11.0°,        11.5°, and 16.6° (form 3).

3) Another embodiment relates to crystalline forms of COMPOUND⋅HClaccording to embodiment 1), characterized by

-   -   a. the presence of peaks in the X-ray powder diffraction diagram        at the following angles of refraction 2θ: 4.0°, 5.0°, 5.9°,        11.7°, 15.3°, 16.9°, 19.3°, 19.7°, and 20.7° (form 1); or    -   b. the presence of peaks in the X-ray powder diffraction diagram        at the following angles of refraction 2θ: 5.2°, 6.8°, 8.0°,        10.3°, 10.8°, 12.7°, 15.4°, 16.2°, 20.3°, and 21.7° (form 2); or    -   c. the presence of peaks in the X-ray powder diffraction diagram        at the following angles of refraction 2θ: 5.5°, 7.2°, 11.0°,        11.5°, 14.4°, 16.6°, 18.1°, 21.1°, and 22.0° (form 3).

4) Another embodiment relates to a crystalline form of COMPOUND⋅HClaccording to embodiment 1), characterized by the presence of peaks inthe X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 4.0°, 5.0°, and 15.3°.

5) Another embodiment relates to a crystalline form of COMPOUND⋅HClaccording to embodiment 1), characterized by the presence of peaks inthe X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 4.0°, 5.0°, 11.7°, 15.3°, and 19.3°.

6) Another embodiment relates to a crystalline form of COMPOUND⋅HClaccording to embodiment 1), characterized by the presence of peaks inthe X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 4.0°, 5.0°, 5.9°, 11.7°, 15.3°, 16.9°, 19.3°, 19.7°, and20.7°.

7) Another embodiment relates to a crystalline form of COMPOUND⋅HClaccording to embodiment 1), which essentially shows the X-ray powderdiffraction pattern as depicted in FIG. 1.

8) Another embodiment relates to a crystalline form of COMPOUND⋅HClaccording to embodiment 1), characterized by the presence of peaks inthe X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 5.2°, 6.8°, and 10.3°.

9) Another embodiment relates to a crystalline form of COMPOUND⋅HClaccording to embodiment 1), characterized by the presence of peaks inthe X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 5.2°, 6.8°, 10.3°, 10.8°, and 15.4°.

10) Another embodiment relates to a crystalline form of COMPOUND⋅HClaccording to embodiment 1), characterized by the presence of peaks inthe X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 5.2°, 6.8°, 8.0°, 10.3°, 10.8°, 12.7°, 15.4°, 16.2°,20.3°, and 21.7°.

11) Another embodiment relates to a crystalline form of COMPOUND⋅HClaccording to embodiment 1), which essentially shows the X-ray powderdiffraction pattern as depicted in FIG. 2.

12) Another embodiment relates to a crystalline form of COMPOUND⋅HClaccording to embodiment 1), characterized by the presence of peaks inthe X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 5.5°, 11.0°, and 16.6°.

13) Another embodiment relates to a crystalline form of COMPOUND⋅HClaccording to embodiment 1), characterized by the presence of peaks inthe X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 5.5°, 7.2°, 11.0°, 11.5°, and 16.6°.

14) Another embodiment relates to a crystalline form of COMPOUND⋅HClaccording to embodiment 1), characterized by the presence of peaks inthe X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 5.5°, 7.2°, 11.0°, 11.5°, 14.4°, 16.6°, 18.1°, 21.1°, and22.0°.

15) Another embodiment relates to a crystalline form of COMPOUND⋅HClaccording to embodiment 1), which essentially shows the X-ray powderdiffraction pattern as depicted in FIG. 3.

16) Another embodiment relates to a crystalline form, such as anessentially pure crystalline form, of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride (COMPOUND⋅HCl) obtainable by:

-   -   a. addition of aq. 33% HCl (5.1 vol.) to a solution of butyl        4-((R)-3-(diethoxyphosphoryl)-2-(6-((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carboxamido)propanoyl)piperazine-1-carboxylate        in a mixture of DCM and THF (5.5 vol.);    -   b. stirring for 4 to 12 h at a temperature of 20 to 30° C.;    -   c. addition of water (8.2 vol.) and DCM (8.2 vol.) at a        temperature of 20 to 30° C.;    -   d. separation of layers and extraction with DCM (8.2 vol.);    -   e. removal of solvent by distillation at T_(i)=50° C., addition        of acetone (8.7 vol.) and further removal of solvent by        distillation at T_(i)=50° C. until a final amount of 7.0 vol.        remains;    -   f. addition of acetone (18.5 vol.) at T_(i)=50° C.;    -   g. addition of water (0.5 vol.) at T_(i)=50° C. within 30 min        and stirring at T_(i)=56° C. for 3.5 h;    -   h. cooling to 20 to 30° C. within 2 h and stirring at 20 to        30° C. for 1.5 h; and    -   i. isolation of the obtained solid residue.

17) Another embodiment relates to a crystalline form of COMPOUND⋅HClaccording to embodiment 16), characterized by the presence of peaks inthe X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 4.0°, 5.0°, and 15.3°.

18) Another embodiment relates to a crystalline form of COMPOUND⋅HClaccording to embodiment 16), characterized by the presence of peaks inthe X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 4.0°, 5.0°, 11.7°, 15.3°, and 19.3°.

19) Another embodiment relates to a crystalline form of COMPOUND⋅HClaccording to embodiment 16), characterized by the presence of peaks inthe X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 4.0°, 5.0°, 5.9°, 11.7°, 15.3°, 16.9°, 19.3°, 19.7°, and20.7°.

20) Another embodiment relates to a crystalline form of COMPOUND⋅HClaccording to embodiment 16), which essentially shows the X-ray powderdiffraction pattern as depicted in FIG. 1.

21) Another embodiment relates to the crystalline form of COMPOUND⋅HClaccording to any one of embodiments 4) to 7), obtainable by the processof embodiment 16).

22) Another embodiment relates to a crystalline form, such as anessentially pure crystalline form, of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride (COMPOUND⋅HCl) obtainable by:

-   -   a) equilibration of a sample of COMPOUND⋅HCl in a crystalline        form according to any one of embodiments 4) to 7) at RH>90% and        at about RT; and    -   b) equilibration of the obtained sample at about RH=40% and at        about RT.

Especially, the first equilibration step requires about 3 days and thesecond equilibration step requires about 1 day.

23) Another embodiment relates to a crystalline form of COMPOUND⋅HClaccording to embodiment 22), characterized by the presence of peaks inthe X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 5.2°, 6.8°, and 10.3°.

24) Another embodiment relates to a crystalline form of COMPOUND⋅HClaccording to embodiment 22), characterized by the presence of peaks inthe X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 5.2°, 6.8°, 10.3°, 10.8°, and 15.4°.

25) Another embodiment relates to a crystalline form of COMPOUND⋅HClaccording to embodiment 22), characterized by the presence of peaks inthe X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 5.2°, 6.8°, 8.0°, 10.3°, 10.8°, 12.7°, 15.4°, 16.2°,20.3°, and 21.7°.

26) Another embodiment relates to a crystalline form of COMPOUND⋅HClaccording to embodiment 22), which essentially shows the X-ray powderdiffraction pattern as depicted in FIG. 2.

27) Another embodiment relates to the crystalline form of COMPOUND⋅HClaccording to any one of embodiments 8) to 11), obtainable by theprocesses of embodiment 22).

28) Another embodiment relates to a crystalline form, such as anessentially pure crystalline form, of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride (COMPOUND⋅HCl) obtainable by:

-   -   a) equilibration of a sample of COMPOUND⋅HCl in a crystalline        form according to any one of embodiments 8) to 11) in a dry        nitrogen gas stream at about RT; and    -   b) equilibration of the obtained sample at about RH=40% and at        about RT.

Especially, the first equilibration step requires about 1 day for a 100mg sample at a gas stream of about 400 mL/min and the secondequilibration step requires about 1 day.

29) Another embodiment relates to a crystalline form of COMPOUND⋅HClaccording to embodiment 28), characterized by the presence of peaks inthe X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 5.5°, 11.0°, and 16.6°.

30) Another embodiment relates to a crystalline form of COMPOUND⋅HClaccording to embodiment 28), characterized by the presence of peaks inthe X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 5.5°, 7.2°, 11.0°, 11.5°, and 16.6°.

31) Another embodiment relates to a crystalline form of COMPOUND⋅HClaccording to embodiment 28), characterized by the presence of peaks inthe X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 5.5°, 7.2°, 11.0°, 11.5°, 14.4°, 16.6°, 18.1°, 21.1°, and22.0°.

32) Another embodiment relates to a crystalline form of COMPOUND⋅HClaccording to embodiment 28), which essentially shows the X-ray powderdiffraction pattern as depicted in FIG. 3.

33) Another embodiment relates to the crystalline form of COMPOUND⋅HClaccording to any one of embodiments 12) to 15), obtainable by theprocesses of embodiment 28).

34) Another embodiment relates to a crystalline form of COMPOUND⋅HClaccording to any one of embodiments 4) to 7) or 16) to 21), whichessentially shows a gravimetric moisture sorption profile (sorptioncycle) as depicted in FIG. 4, wherein the gravimetric moisture sorptionprofile is measured at 25° C.

35) Another embodiment relates to a crystalline form of COMPOUND⋅HClaccording to any one of embodiments 8) to 11) or 22) to 27), whichessentially shows a gravimetric moisture sorption profile (desorptioncycle) as depicted in FIG. 5, wherein the gravimetric moisture sorptionprofile is measured at 25° C.

36) Another embodiment relates to a crystalline form of COMPOUND⋅HClaccording to any one of embodiments 12) to 15) or 28) to 33), whichessentially shows a gravimetric moisture sorption profile (sorptioncycle) as depicted in FIG. 6, wherein the gravimetric moisture sorptionprofile is measured at 25° C.

37) A process for the preparation of COMPOUND⋅HCl in a crystalline formaccording to any one of embodiments 1) to 7), wherein the processcomprises the following steps:

-   -   a. addition of acetone (10 to 30 vol.) to a solution comprising        COMPOUND⋅HCl and a non-polar solvent (0.5 to 3.0 vol.; 0.5 to        3.0 L per kg COMPOUND⋅HCl) at 45 to 60° C., wherein the        non-polar solvent is selected from (C₁₋₂)chloroalkane;    -   b. addition of water (0.3 to 0.7 vol.) at 45 to 60° C.;    -   c. stirring of the mixture under cooling from a temperature of        45 to 60° C. to a temperature at or below 30° C. for at least 1        h; and    -   d. isolation of the obtained crystalline material.

38) A process according to embodiment 37), wherein the amount of addedacetone in step a. is about 20 vol.

39) A process according to any one of embodiments 37) or 38), whereinthe amount of the non-polar solvent in step a. is 1.0 to 2.0 vol. andwherein the non-polar solvent is dichloromethane.

40) A process according to any one of embodiments 37) to 39), whereinthe amount of the added water in step b. is 0.4 to 0.6 vol. (andespecially 0.5 vol.).

41) A process according to any one of embodiments 37) to 40), whereinthe mixture is stirred in step c. between 1 and 4 h at a temperature of45 to 60° C. and is subsequently cooled to a temperature between 20 and30° C. (especially 25° C.) during 1 to 2 h.

42) A process according to any one of embodiments 37) to 41), whereinthe isolation in step d. is done by filtration.

43) A process according to any one of embodiments 37) to 42), whereinthe solution comprising COMPOUND⋅HCl and a non-polar solvent used instep a. is obtained by a process comprising the steps:

-   -   a. coupling of        (S)-6-(3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carboxylic        acid, or a salt thereof (especially a sodium salt thereof), with        butyl        (R)-4-(2-amino-3-(diethoxyphosphoryl)propanoyl)piperazine-1-carboxylate        in the presence of an amide coupling agent;    -   b. extraction with a solvent mixture comprising        -   (C₁₋₂)chloroalkane (especially dichloromethane); and        -   water or an aqueous solution of an inorganic salt            (especially an aqueous sodium hydrogencarbonat solution)    -   c. addition of aqueous hydrochloric acid and stirring of the        mixture;    -   d. extraction with a solvent mixture comprising        -   (C₁₋₂)chloroalkane (especially dichloromethane); and        -   water or an aqueous solution of an inorganic salt            (especially water); and    -   e. removal of solvents until the amount of (C₁₋₂)chloroalkane        equals 0.5 to 3.0 L per kg (especially 1.0 to 2.0 L per kg)        COMPOUND⋅HCl.

Based on the dependencies of the different embodiments 1) to 43) asdisclosed hereinabove, the following embodiments are thus possible andintended and herewith specifically disclosed in individualised form:

1, 2+1, 3+1, 4+1, 5+1, 6+1, 7+1, 8+1, 9+1, 10+1, 11+1, 12+1, 13+1, 14+1,15+1, 16, 17+16, 18+16, 19+16, 20+16, 21+4+1, 21+5+1, 21+6+1, 21+7+1,22, 23+22, 24+22, 25+22, 26+22, 27+8+1, 27+9+1, 27+10+1, 27+11+1, 28,29+28, 30+28, 31+28, 32+28, 33+12+1, 33+13+1, 33+14+1, 33+15+1, 34+4+1,34+5+1, 34+6+1, 34+7+1, 34+16, 34+17+16, 34+18+16, 34+19+16, 34+20+16,34+21+4+1, 34+21+5+1, 34+21+6+1, 34+21+7+1,35+8+1, 35+9+1, 35+10+1,35+11+1, 35+22, 35+23+22, 35+24+22, 35+25+22, 35+26+22, 35+27+8+1,35+27+9+1, 35+27+10+1, 35+27+11+1, 36+12+1, 36+13+1, 36+14+1, 36+15+1,36+28, 36+29+28, 36+30+28, 36+31+28, 36+32+28, 36+33+12+1, 36+33+13+1,36+33+14+1, 36+33+15+1, 37, 38+37, 39+37, 39+38+37, 40+37, 40+38+37,40+39+37, 40+39+38+37, 41+37, 41+38+37, 41+39+37, 41+39+38+37, 41+40+37,41+40+38+37, 41+40+39+37, 41+40+39+38+37, 42+37, 42+38+37, 42+39+37,42+39+38+37, 42+40+37, 42+40+38+37, 42+40+39+37, 42+40+39+38+37,42+41+37, 42+41+38+37, 42+41+39+37, 42+41+39+38+37, 42+41+40+37,42+41+40+38+37, 42+41+40+39+37, 42+41+40+39+38+37, 43+37, 43+38+37,43+39+37, 43+39+38+37, 43+40+37, 43+40+38+37, 43+40+39+37,43+40+39+38+37, 43+41+37, 43+41+38+37, 43+41+39+37, 43+41+39+38+37,43+41+40+37, 43+41+40+38+37, 43+41+40+39+37, 43+41+40+39+38+37,43+42+37, 43+42+38+37, 43+42+39+37, 43+42+39+38+37, 43+42+40+37,43+42+40+38+37, 43+42+40+39+37, 43+42+40+39+38+37, 43+42+41+37,43+42+41+38+37, 43+42+41+39+37, 43+42+41+39+38+37, 43+42+41+40+37,43+42+41+40+38+37, 43+42+41+40+39+37,43+42+41+40+39+38+37;

in the list above the numbers refer to the embodiments according totheir numbering provided hereinabove whereas “+” indicates thedependency from another embodiment. The different individualisedembodiments are separated by commas. In other words, “21+4+1” forexample refers to embodiment 21) depending on embodiment 4), dependingon embodiment 1), i.e. embodiment “21+4+1” corresponds to embodiment 1)further characterised by the features of the embodiments 4) and 21).

For avoidance of any doubt, whenever one of the above embodiments refersto “peaks in the X-ray powder diffraction diagram at the followingangles of refraction 2θ”, said X-ray powder diffraction diagram isobtained by using combined Cu Kα1 and Kα2 radiation, without Kα2stripping; and it should be understood that the accuracy of the 2θvalues as provided herein is in the range of +/−0.1-0.2°. Notably, whenspecifying an angle of refraction 2theta (2θ) for a peak in theinvention embodiments and the claims, the 2θ value given is to beunderstood as an interval from said value minus 0.2° to said value plus0.2° (2θ+/−0.2°); and preferably from said value minus 0.1° to saidvalue plus 0.1° (2θ+/−0.1°).

Where the plural form is used for compounds, solids, pharmaceuticalcompositions, diseases and the like, this is intended to mean also asingle compound, solid, pharmaceutical composition, disease or the like.

Definitions provided herein are intended to apply uniformly to thesubject matter as defined in any one of embodiments 1) to 43), and,mutatis mutandis, throughout the description and the claims unless anotherwise expressly set out definition provides a broader or narrowerdefinition. It is well understood that a definition or preferreddefinition of a term or expression defines and may replace therespective term or expression independently of (and in combination with)any definition or preferred definition of any or all other terms orexpressions as defined herein.

The term “(C₁₋₂)chloroalkane” refers to an alkane group containing oneor two carbon atoms in which one or more (and possibly all) hydrogenatoms have been replaced with chlorine. For example a (C₁₋₂)chloroalkanegroup contains one or two carbon atoms in which one to six (especiallytwo) hydrogen atoms have been replaced with chlorine. Preferred examplesof (C₁₋₂)chloroalkane groups are dichloromethane and 1,2-dichloroethane(and especially dichloromethane).

The term “amide coupling agent” refers to a compound that promotes theformation of a chemical bond (amide bond) between the —COOH group of acarboxylic acid and the —NH₂ group of an amine. Representative examplesof amide coupling agents are carbodiimides (such asdicyclohexylcarbodiimide, diisopropylcarbodiimide or1-ethyl-3-(3-dimethylamino-propyl)carbodiimide) in the presence orabsence of an additive such as 1-hydroxy-benzotriazole,1-hydroxy-7-aza-1 H-benzotriazole or N-hydroxysuccinimide; phosphoniumreagents (such as benzotriazol-1-yloxy-tris(dimethylamino)-phosphoniumhexafluoro-phosphate or benzotriazol-1-yloxy-tripyrrolidino-phosphoniumhexafluorophosphate); aminium reagents (such as2-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethylaminiumtetra-fluoroborate,2-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethylaminiumhexafluorophosphate or2-(7-aza-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethylaminiumhexafluorophosphate); and 2-propanephosphonic acid anhydride; preferredis 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide in the presence of1-hydroxy-benzotriazole.

The term “enantiomerically enriched” is understood in the context of thepresent invention to mean especially that at least 90, preferably atleast 95, and most preferably at least 99 per cent by weight of theCOMPOUND (or of COMPOUND⋅HCl) are present in form of one enantiomer ofthe COMPOUND (or of COMPOUND⋅HCl). It is understood that any referenceto “COMPOUND” (or to “ COMPOUND⋅HCl”) refers to4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionylypiperazine-1-carboxylicacid (or to its HCl salt) in enantiomerically enriched or in pure form.

The term “essentially pure” is understood in the context of the presentinvention to mean especially that at least 90, preferably at least 95,and most preferably at least 99 per cent by weight of the crystals ofCOMPOUND⋅HCl are present in a crystalline form according to the presentinvention.

When defining the presence of peak in e.g. an X-ray powder diffractiondiagram, a common approach is to do this in terms of the S/N ratio(S=signal, N=noise). According to this definition, when stating that apeak has to be present in a X-ray powder diffraction diagram, it isunderstood that the peak in the X-ray powder diffraction diagram isdefined by having an S/N ratio (S=signal, N=noise) of greater than x (xbeing a numerical value greater than 1), usually greater than 2,especially greater than 3.

In the context with stating that the crystalline form essentially showsan X-ray powder diffraction pattern as depicted in FIG. 1, 2, or 3,respectively, the term “essentially” means that at least the major peaksof the diagram depicted in said figures, i.e. those having a relativeintensity of more than 20%, especially more than 10%, as compared to themost intense peak in the diagram, have to be present. However, theperson skilled in the art of X-ray powder diffraction will recognizethat relative intensities in X-ray powder diffraction diagrams may besubject to strong intensity variations due to preferred orientationeffects.

The term “equilibration”, as used in the context of “equilibration of asample of COMPOUND⋅HCl”, refers to a process step of keeping a samplefor an equilibration time under specific conditions, such as aspecifically given relative humidity, a specifically given gas streamand/or a specifically given temperature, wherein the term “equilibrationtime” refers to the time that is required to obtain an essentiallyconstant content of water in the sample. The content of water is“essentially constant” if the change in the water content is less than5% if the sample is kept for 24 h under the given specific conditions.

Unless used regarding temperatures, the term “about” placed before anumerical value “X” refers in the current application to an intervalextending from X minus 10% of X to X plus 10% of X, and preferably to aninterval extending from X minus 5% of X to X plus 5% of X; mostpreferred is X. In the particular case of temperatures, the term “about”placed before a temperature “Y” refers in the current application to aninterval extending from the temperature Y minus 10° C. to Y plus 10° C.,preferably to an interval extending from Y minus 3° C. to Y plus 3° C.;most preferred is Y. Room temperature means a temperature of about 25°C.

Whenever the word “between” or “to” is used to describe a numericalrange, it is to be understood that the end points of the indicated rangeare explicitly included in the range. For example: if a temperaturerange is described to be between 40° C. and 80° C. (or 40° C. to 80°C.), this means that the end points 40° C. and 80° C. are included inthe range; or if a variable is defined as being an integer between 1 and4 (or 1 to 4), this means that the variable is the integer 1, 2, 3, or4.

It is understood that4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionylypiperazine-1-carboxylicacid butyl ester hydrochloride (or COMPOUND⋅HCl) refers to ahydrochloride salt of COMPOUND wherein the salt contains about 1 molarequivalent of HCl per molar equivalent of COMPOUND, especially 0.98 to1.02 molar equivalent of HCl per molar equivalent of COMPOUND andnotably 1.00 molar equivalent of HCl per molar equivalent of COMPOUND.

The expression % w/w refers to a percentage by weight compared to thetotal weight of the composition considered. Likewise, the expression v/vrefers to a ratio by volume of the two components considered.

The crystalline forms, especially the essentially pure crystallineforms, of COMPOUND⋅HCl according to any one of embodiments 1) to 36) canbe used as medicaments, e.g. in the form of pharmaceutical compositionsfor enteral (such especially oral) or parenteral administration(including topical application or inhalation).

44) Another embodiment thus relates to a crystalline form of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride according to any one of embodiments 1) to36) for use as a medicament.

45) Another embodiment relates to COMPOUND, or a pharmaceuticallyacceptable salt thereof, for use as a medicament, wherein COMPOUND, or apharmaceutically acceptable salt thereof, is obtained from a crystallineform of COMPOUND⋅HCl according to any one of embodiments 1) to 36).

The term “pharmaceutically acceptable salt” refers to a salt thatretains the desired biological activity of the subject compound andexhibits minimal undesired toxicological effects. Such salts includeinorganic or organic acid and/or base addition salts depending on thepresence of basic and/or acidic groups in the subject compound. Forreference see for example ‘Handbook of Pharmaceutical Salts. Properties,Selection and Use.’, P. Heinrich Stahl, Camille G. Wermuth (Eds.),Wiley-VCH, 2008, and ‘Pharmaceutical Salts and Co-crystals’, JohanWouters and Luc Quéré (Eds.), RSC Publishing, 2012.

The crystalline solid, especially the essentially pure crystallinesolid, of COMPOUND⋅HCl according to any one of embodiments 1) to 36) maybe used as single component or as mixture with other crystalline formsor amorphous form of COMPOUND⋅HCl.

The production of the pharmaceutical compositions can be effected in amanner which will be familiar to any person skilled in the art (see forexample Remington, The Science and Practice of Pharmacy, 21st Edition(2005), Part 5, “Pharmaceutical Manufacturing” [published by LippincottWilliams & Wilkins]) by bringing the crystalline form of the presentinvention, optionally in combination with other therapeutically valuablesubstances, into a galenical administration form together with suitable,non-toxic, inert, pharmaceutically acceptable solid or liquid carriermaterials and, if desired, usual pharmaceutical adjuvants.

46) A further embodiment of the invention relates to pharmaceuticalcompositions comprising as active ingredient a crystalline form ofCOMPOUND⋅HCl according to any one of embodiments 1) to 36), and at leastone pharmaceutically acceptable carrier material.

47) A further embodiment of the invention relates to pharmaceuticalcompositions comprising as active ingredient COMPOUND, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier material, wherein COMPOUND, or apharmaceutically acceptable salt thereof, is obtained from a crystallineform of COMPOUND⋅HCl according to any one of embodiments 1) to 36).

48) A further embodiment of the invention relates to a crystalline formof COMPOUND⋅HCl according to any one of embodiments 1) to 36), for usein the manufacture of a pharmaceutical composition, wherein saidpharmaceutical composition comprises as active ingredient theCOMPOUND⋅HCl, and at least one pharmaceutically acceptable carriermaterial.

49) A further embodiment of the invention relates to COMPOUND, or apharmaceutically acceptable salt thereof, for use in the manufacture ofa pharmaceutical composition, wherein said pharmaceutical compositioncomprises as active ingredient the COMPOUND, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier material, wherein the COMPOUND is obtained from a crystallineform of COMPOUND⋅HCl according to any one of embodiments 1) to 36).

50) A further embodiment of the invention relates to a crystalline formof COMPOUND⋅HCl according to any one of embodiments 1) to 36), for usein the prevention/prophylaxis or treatment of diseases selected from thegroup consisting of acute arterial thrombosis.

51) A preferred embodiment of the invention relates to a crystallineform of COMPOUND⋅HCl according to any one of embodiments 1) to 36), foruse in the prevention/prophylaxis or treatment of diseases selected fromthe group consisting of acute coronary syndromes, peripheral ischaemia,amaurosis, ischaemic stroke and transient ischaemic attack.

52) A most preferred embodiment of the invention relates to acrystalline form of COMPOUND⋅HCl according to any one of embodiments 1)to 36), for use in the prevention/prophylaxis or treatment of acutecoronary syndromes.

53) A further embodiment of the invention relates to COMPOUND, or apharmaceutically acceptable salt thereof, for use in theprevention/prophylaxis or treatment of a disease selected from thediseases according to any one of embodiments 50) to 52), wherein theCOMPOUND, or a pharmaceutically acceptable salt thereof, is obtainedfrom a crystalline form of COMPOUND⋅HCl according to any one ofembodiments 1) to 36).

54) A further embodiment of the invention relates to a crystalline formof COMPOUND⋅HCl according to any one of embodiments 1) to 36), for usein the manufacture of a pharmaceutical composition for theprevention/prophylaxis or treatment of diseases selected from the groupconsisting of acute arterial thrombosis.

55) A preferred embodiment of the invention relates to a crystallineform of COMPOUND⋅HCl according to any one of embodiments 1) to 36), foruse in the manufacture of a pharmaceutical composition for theprevention/prophylaxis or treatment of diseases selected from the groupconsisting of acute coronary syndromes, peripheral ischaemia, amaurosis,ischaemic stroke and transient ischaemic attack.

56) A most preferred embodiment of the invention relates to acrystalline form of COMPOUND⋅HCl according to any one of embodiments 1)to 36), for use in the manufacture of a pharmaceutical composition forthe prevention/prophylaxis or treatment of acute coronary syndromes.

57) A further embodiment of the invention relates to COMPOUND, or apharmaceutically acceptable salt thereof, for use in the manufacture ofa pharmaceutical composition for the prevention/prophylaxis or treatmentof a disease selected from the diseases according to any one ofembodiments 54) to 56), wherein the COMPOUND, or a pharmaceuticallyacceptable salt thereof, is obtained from a crystalline form ofCOMPOUND⋅HCl according to any one of embodiments 1) to 36).

58) A further embodiment of the invention relates to pharmaceuticalcompositions according to embodiment 46), for use in theprevention/prophylaxis or treatment of diseases selected from the groupconsisting of acute arterial thrombosis.

59) A preferred embodiment of the invention relates to pharmaceuticalcompositions according to embodiment 46), for use in theprevention/prophylaxis or treatment of diseases selected from the groupconsisting of acute coronary syndromes, peripheral ischaemia, amaurosis,ischaemic stroke and transient ischaemic attack.

60) A most preferred embodiment of the invention relates topharmaceutical compositions according to embodiment 46), for use in theprevention/prophylaxis or treatment of acute coronary syndromes.

61) A further embodiment of the invention relates to pharmaceuticalcompositions according to embodiment 47), for use in theprevention/prophylaxis or treatment of a disease selected from thediseases according to any one of embodiments 58) to 60).

The present invention also relates to a method for theprevention/prophylaxis or treatment of a disease or disorder mentionedherein, comprising administering to a subject a pharmaceutically activeamount of a crystalline form of COMPOUND⋅HCl according to any one ofembodiments 1) to 36), or of a pharmaceutical composition according toembodiment 46).

The present invention also relates to a method for theprevention/prophylaxis or treatment of a disease or disorder mentionedherein, comprising administering to a subject a pharmaceutically activeamount of the COMPOUND, or a pharmaceutically acceptable salt thereof,wherein the COMPOUND, or a pharmaceutically acceptable salt thereof, isobtained from a crystalline form of COMPOUND⋅HCl according to any one ofembodiments 1) to 36), or of the pharmaceutical composition according toembodiment 47).

Experimental Procedures:

Abbreviations (as used hereinbefore or hereinafter):

AP Aqueous layer

aq. Aqueous

Bu Butyl such as in n-Bu=n-butyl

conc. Concentrated

DCM Dichloromethane

EDCl 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

eq Equivalent(s)

Et Ethyl

EtOAc Ethyl acetate

EtOH Ethanol

Fig Figure

h Hour(s)

¹H-NMR Nuclear magnetic resonance of the proton

HOBt 1-Hydroxy-benzotriazole mono hydrate

HPLC High performance liquid chromatography

IPC In-process control

LC-MS Liquid chromatography Mass Spectrometry

Me Methyl

MeCN Acetonitrile

MeOH Methanol

mW milli-Watt

min Minute(s)

MS Mass spectrometry

N Normality

NMR Nuclear magnetic resonance

prep. Preparative

RH relative humidity

RT Room temperature

sat. Saturated

sec Second(s)

T_(e) External temperature

T_(i) Internal temperature

TFA trifluoroacetic acid

THF Tetrahydrofuran

t_(R) Retention time

UPLC Ultra Performance Liquid Chromatography

UV Ultra violet

vol. L solvent per kg starting material

XRPD X-ray powder diffraction

All solvents and reagents are used as obtained from commercial sourcesunless otherwise indicated.

Temperatures are indicated in degrees Celsius (° C.). Unless otherwiseindicated, the reactions take place at room temperature (RT).

In mixtures, relations of parts of solvent or eluent or reagent mixturesin liquid form are given as volume relations (v/v), unless indicatedotherwise.

Compounds described in the invention are characterized by UPLC andchiral HPLC (retention time t_(R) is given in min using the conditionslisted below).

Analytical UPLC conditions as used in the Examples below:

UPLC analyses are performed using the following elution condition:

Analytical UPLC on YMC Triart ExRS (Part. No. TAR08S03-1003PTH) column(100mm×3.0 mm, 3 μm); Gradient of 20 mM Ammonium acetate+10 mM NH₄PF₆buffer/Acetonitrile 95/5 (A) and Acetonitrile/Ammonium acetate 10 mM (B)from 8% to 100% B over 19 min; flow rate 0.5 ml/min, detection at 210nm.

Analytical HPLC over a chiral stationary phase are performed on aChiralpak AD-H (4.6×250 mm, 5 μm) column. Typical conditions of chiralHPLC are an isocratic mixture of Hexane/Ethanol/TFA (80:20:0.1 v/v/v),at a flow rate of 0.8 mL/min., at 40° C.; detection at 247 nm.

X-Ray Powder Diffraction Analysis (XRPD)

X-ray powder diffraction patterns were collected on a Bruker D8 AdvanceX-ray diffractometer equipped with a Lynxeye detector operated withCuKα-radiation in reflection mode (coupled two Theta/Theta). Typically,the X-ray tube was run at of 40 kV/40 mA. A step size of 0.02° (20) anda step time of 76.8 sec over a scanning range of 3-50° in 2θ wereapplied. The divergence slits were set to fixed 0.3°. Powders wereslightly pressed into a silicon single crystal sample holder with depthof 0.5 mm and samples were rotated in their own plane during themeasurement. Diffraction data are reported without application of Kα2stripping. The accuracy of the 2θ values as provided herein is in therange of +/−0.1-0.2° as it is generally the case for conventionallyrecorded X-ray powder diffraction patterns.

Gravimetric Vapour Sorption (GVS) Analysis

Measurements were performed on an IGASORP Model HAS-036-080 moisturesorption instrument (Hiden Isochema, Warrington, UK) operated instepping mode at 25° C. The sample was allowed to equilibrate at thestarting relative humidity (RH) before starting a pre-defined humidityprogram in steps of 5% ARH and with a maximal equilibration time of 24hours per step. About 20 to 30 mg of each sample was used.

I-Chemistry

(S)-6-(3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carboxylic acid,butyl(R)-4-(2-amino-3-(diethoxyphosphoryl)propanoyl)piperazine-1-carboxylateand4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester (COMPOUND) can be prepared according to the proceduresgiven in WO 2009/069100 (example 2) or Caroff E et al., J. Med. Chem.2015; 58:9133-9153.(S)-6-(3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carboxylic acidcan be transferred into sodium(S)-6-(3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carboxylate inpresence of aqueous sodium hydroxide.

II. Preparation of Crystalline Forms of COMPOUND⋅HCl

EXAMPLE 1A Preparation and Characterization of COMPOUND⋅HCl inCrystalline Form 1

A 15 L reactor was charged with sodium(S)-6-(3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carboxylate (584g, 1.82 mol) and 1-hydroxy-benzotriazole mono hydrate (HOBt) (274 g, 1.1eq.). Water (1305 mL, 2.0 vol.) was added. The pH of the suspension was5-6. Butyl(R)-4-(2-amino-3-(diethoxyphosphoryl)propanoyl)piperazine-1-carboxylate(665.7 g, 1.0 eq) was dissolved in tetrahydrofurane (THF) (1960 ml, 3.0vol.). The solution was added to the reaction at 20 to 30° C. during 5to 10 min. A solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(EDCl) (389 g, 1.2 eq.) in water (1305 ml, 2.0 vol.) was added to thereaction at 20 to 30° C. during 15 to 30 min. The pH of the reactionstayed between 6-7. The reaction was stirred during 4 h at 20 to 30° C.An IPC showed 93% conversion. The reaction was diluted withdichloromethane (DCM) (3265 ml, 5.0 vol.) and ½ sat. aq. sodiumhydrogencarbonat solution (3265 ml, 5.0 vol.). The layers wereseparated. The organic layer was washed again with ½ sat. aq. sodiumhydrogencarbonat solution (3265 ml, 5.0 vol.). The layers wereseparated. An IPC showed the complete removal of HOBt. The organic layerwas washed with aq. 10% citric acid (3265 ml, 5.0 vol.). In total 3.75 Lof solvents were distilled off at minimal 800 mbar and T_(e)=75 to 80°C. during 40 min. The residual solution was cooled to 20 to 30° C. Aq.32% HCl (3 L, 19 eq.) was added during 5 to 10 min at 20 to 30° C. AnIPC after 4 h of stirring showed complete hydrolysis. Water (5.2 L, 8vol.) was added at 20 to 30° C. The reaction was diluted with DCM (5.2L, 8 vol.). The layers were separated. The aqueous layer was extractedagain 2× with DCM (2× 5.2 L, 8 vol.). All DCM layers were combined andfiltered through a polycap 75 HD filter. In total 14 L of solvents weredistilled off during 2 h at atmospheric pressure and T_(e)=75 to 80° C.Acetone (21.6 L, 33 vol.) was added to the refluxing reaction mixture atT_(e)=70 to 75° C. To the refluxing fine suspension water (325 mL, 0.5vol.) was added. The fine, pale suspension was stirred at reflux during1.5 h and a thick white slurry was obtained. The slurry was cooled toT_(i)=25° C. during 1 h (ramp). The solid product was isolated byfiltration. The filter cake was rinsed with acetone (4.5 L, 7 vol.) andwas dried by blowing nitrogen through it to give 750 g (69%) of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride as a white solid.

TABLE 1 Characterisation data for COMPOUND•HCl in crystalline form 1Technique Data Summary Remarks XRPD Crystalline see FIG. 1 1H-NMRConsistent Elemental analysis Corresponds Purity (UPLC, Area %) 98.6%Moisture sorption at Profile measured from see FIG. 4 25° C. low RH tohigh RH

EXAMPLE 1B Preparation and Characterization of COMPOUND⋅HCl inCrystalline Form 1

An enamelled reactor was charged with water (10.5 L; 1.6 vol.), sodium(S)-6-(3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carboxylate (6.06kg; 18.87 mol, 1.12 eq) and 1-hydroxy-benzotriazole mono hydrate (HOBt)(2.71 kg; 17.70 mol; 1.08 eq.). The resulting white suspension wasstirred during 60 min at 21° C. A yellow solution of butyl(R)-4-(2-amino-3-(diethoxyphosphoryl)propanoyl)piperazine-1-carboxylate(6.47 kg, 16.45 mol, 1.0 eq.) in THF (41 kg, 46.6 L, 7.2 vol.) wastransferred into a stirring tank via inline filter. After addition ofthis solution into the reactor within 12 min at 20° C. a solution of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCl) (4.00 kg; 20.8 mol;1.26 eq.) in water (13.5 L; 2.1 vol.) was added within 13 min at 20° C.The reaction was stirred during 64 h at 20° C. At 20° C. aq. 3.7% NaHCO₃(32 L; 5.0 vol.) was added into the reactor followed by dichloromethane(DCM) (32 L; 5.0 vol.). The mixture was stirred during 10 min at 20° C.After layer separation the pH of the aqueous layer (AP) was 8-9. The APwas extracted again with DCM (16 L; 2.5 vol.). The combined organiclayers were charged into the reactor (total volume=94 L) and were washedwith aq. 3.7% NaHCO₃ (32 L; 5.0 vol.). After layer separation the pH was10. The resulting organic layer was washed with aq. 10% citric acid (32L; 5.0 vol.). The yellow solution was concentrated to a final volume of5.5 vol. of butyl4-((R)-3-(diethoxyphosphoryl)-2-(6-((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carboxamido)propanoyl)piperazine-1-carboxylateat 55° C. and not below a pressure of 585 mbar. 52 L solvent wereremoved within 5 h.

The concentrated organic solution was treated with aq. 33% HCl (33 L;5.1 vol.). The reaction mixture was stirred during 12 h at 20 to 30° C.An IPC showed complete conversion into free phosphonate. At 20 to 30° C.water (53 L; 8.2 vol.) was added into the reactor followed by DCM (53 L;8.2 vol.). The layers were separated. The aqueous layer was extracted 2×with DCM (53 L; 8.2 vol.). The organic layers were combined andconcentrated at T_(i)=50° C. and a pressure not below 900 mbar. 76 L ofsolvents were removed. Acetone (56 L; 8.7 vol.) was added withoutinterrupting the distillation. The distillation was continued atT_(i)=50° C. until a final amount of 7 vol. remained. The pressure wasnot below 500 mbar. The concentrated solution was diluted with acetone(120 L; 18.5 vol.). The concentrated solution was stirred at T_(i)=50°C. A white suspension was formed. Within 30 minutes the white suspensionwas diluted with water (3.4 L; 0.5 vol.) and was stirred during 3.5 h atT_(i)=56° C. The suspension was cooled to 20 to 30° C. within 2 h andstirred at this temperature for 1.5 h. The thick, white suspension wasfiltered off. The filter cake was washed twice with acetone (2× 24 L;3.7 vol.) and was dried on the filter to give 7.67 kg of((R)-3-(4-(butoxycarbonyl)piperazin-1-yl)-2-(6-((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carboxamido)-3-oxopropyl)phosphonicacid hydrochloride.

TABLE 2 Characterisation data for COMPOUND•HCl in crystalline form 1Technique Data Summary Remarks XRPD Crystalline corresponds to FIG. 11H-NMR Consistent Purity (UPLC, Area %) 99.8% Moisture sorption atProfile measured from corresponds to 25° C. low RH to high RH FIG. 4

EXAMPLE 2 Preparation and Characterization of COMPOUND⋅HCl inCrystalline Form 2

COMPOUND⋅HCl in crystalline form 1 (100mg), as obtained by the processdescribed in example 1A, was allowed to equilibrate at a relativehumidity of >90% and room temperature for 3 days. The sample was thenallowed to equilibrate at 40% RH and room temperature for 1 day to giveCOMPOUND⋅HCl in crystalline form 2.

TABLE 3 Characterisation data for COMPOUND•HCl in crystalline form 2Technique Data Summary Remarks XRPD Crystalline see FIG. 2 1H-NMRConsistent Moisture sorption Profile measured from see FIG. 5 at 25° C.high RH to low RH

EXAMPLE 3A Preparation and Characterization of COMPOUND⋅HCl inCrystalline Form 3

COMPOUND⋅HCl in crystalline form 2 (100mg), as obtained by the processdescribed in example 2, was allowed to equilibrate in a dry nitrogen gasstream (400 mL/min) at room temperature for 1 day. The sample was thenallowed to equilibrate at 40% RH and room temperature for 1 day to giveCOMPOUND⋅HCl in crystalline form 3.

TABLE 4 Characterisation data for COMPOUND•HCl in crystalline form 3Technique Data Summary Remarks XRPD Crystalline see FIG. 3 Moisturesorption Profile measured from see FIG. 6 at 25° C. low RH to high RH

EXAMPLE 3B Preparation and Characterization of COMPOUND⋅HCl inCrystalline Form 3 by Re-Crystallization

An enamelled reactor was rinsed with acetone (20 L).4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yI)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionylypiperazine-1-carboxylicacid butyl ester hydrochloride (1.70 kg), water (1.28 L, 0.75 vol.) andacetone (8.5 L, 5 vol.) were charged and the mixture was heated toT_(i)=40° C. for 34 min. Additional acetone (17 L, 10 vol.) was addedover 47 min. The mixture was further stirred for 37 min at T_(i)=40° C.and cooled to T_(i)=20° C. over 67 min. After 2 h at T_(i)=20° C. thesuspension was slowly filtered over 2 h and the crystalline solid waswashed twice with acetone (2×10 L, 5.9 vol.). Prolonged drying on thesuction filter gave COMPOUND⋅HCl in crystalline form 3.

TABLE 5 Characterisation data for COMPOUND•HCl in crystalline form 3Technique Data Summary Remarks XRPD Crystalline corresponds to FIG. 31H-NMR Consistent

What is claimed is: 1-17. (canceled)
 18. A method for the treatment of adisease selected from the group consisting of acute arterial thrombosis,the method comprising administering to a subject in need thereof apharmaceutical composition comprising as active ingredient4-((R)-2-{[6((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester, or a pharmaceutically acceptable salt thereof, and atleast one pharmaceutically acceptable carrier material, wherein4-((R)-2-{[6((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester, or the pharmaceutically acceptable salt thereof, isobtained from a crystalline form of4-((R)-2-{[6((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride, wherein the crystalline form of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride is characterized by: a. the presence ofpeaks in the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 4.0°, 5.0°, and 15.3°; or b. the presence of peaks in theX-ray powder diffraction diagram at the following angles of refraction2θ: 5.2°, 6.8°, and 10.3°; or c. the presence of peaks in the X-raypowder diffraction diagram at the following angles of refraction 2θ:5.5°, 11.0°, and 16.6°.
 19. The method according to claim 18, whereinthe disease is selected from the group consisting of acute coronarysyndromes, peripheral ischaemia, amaurosis, ischaemic stroke andtransient ischaemic attack.
 20. The method according to claim 18,wherein the disease is an acute coronary syndrome.
 21. The methodaccording to claim 18, wherein the disease is selected from the groupconsisting of unstable angina, non-st-elevation myocardial infarction,and st-elevation myocardial infarction.
 22. The method according toclaim 18, wherein the crystalline form of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride is characterized by: a. the presence ofpeaks in the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 4.0°, 5.0°, 11.7°, 15.3°, and 19.3°; or b. the presenceof peaks in the X-ray powder diffraction diagram at the following anglesof refraction 2θ: 5.2°, 6.8°, 10.3°, 10.8°, and 15.4°; or c. thepresence of peaks in the X-ray powder diffraction diagram at thefollowing angles of refraction 2θ: 5.5°, 7.2°, 11.0°, 11.5°, and 16.6°.23. The method according to claim 19, wherein the crystalline form of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride is characterized by: a. the presence ofpeaks in the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 4.0°, 5.0°, 11.7°, 15.3°, and 19.3°; or b. the presenceof peaks in the X-ray powder diffraction diagram at the following anglesof refraction 2θ: 5.2°, 6.8°, 10.3°, 10.8°, and 15.4°; or c. thepresence of peaks in the X-ray powder diffraction diagram at thefollowing angles of refraction 2θ: 5.5°, 7.2°, 11.0°, 11.5°, and 16.6°.24. The method according to claim 20, wherein the crystalline form of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride is characterized by: a. the presence ofpeaks in the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 4.0°, 5.0°, 11.7°, 15.3°, and 19.3°; or b. the presenceof peaks in the X-ray powder diffraction diagram at the following anglesof refraction 2θ: 5.2°, 6.8°, 10.3°, 10.8°, and 15.4°; or c. thepresence of peaks in the X-ray powder diffraction diagram at thefollowing angles of refraction 2θ: 5.5°, 7.2°, 11.0°, 11.5°, and 16.6°.25. The method according to claim 21, wherein the crystalline form of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride is characterized by: a. the presence ofpeaks in the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 4.0°, 5.0°, 11.7°, 15.3°, and 19.3°; or b. the presenceof peaks in the X-ray powder diffraction diagram at the following anglesof refraction 2θ: 5.2°, 6.8°, 10.3°, 10.8°, and 15.4°; or c. thepresence of peaks in the X-ray powder diffraction diagram at thefollowing angles of refraction 2θ: 5.5°, 7.2°, 11.0°, 11.5°, and 16.6°.26. The method according to claim 18, wherein the crystalline form of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride is characterized by: a. the presence ofpeaks in the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 4.0°, 5.0°, 5.9°, 11.7°, 15.3°, 16.9°, 19.3°, 19.7°, and20.7°; or b. the presence of peaks in the X-ray powder diffractiondiagram at the following angles of refraction 2θ: 5.2°, 6.8°, 8.0°,10.3°, 10.8°, 12.7°, 15.4°, 16.2°, 20.3°, and 21.7°; or c. the presenceof peaks in the X-ray powder diffraction diagram at the following anglesof refraction 2θ: 5.5°, 7.2°, 11.0°, 11.5°, 14.4°, 16.6°, 18.1°, 21.1°,and 22.0°.
 27. The method according to claim 19, wherein the crystallineform of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride is characterized by: a. the presence ofpeaks in the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 4.0°, 5.0°, 5.9°, 11.7°, 15.3°, 16.9°, 19.3°, 19.7°, and20.7°; or b. the presence of peaks in the X-ray powder diffractiondiagram at the following angles of refraction 2θ: 5.2°, 6.8°, 8.0°,10.3°, 10.8°, 12.7°, 15.4°, 16.2°, 20.3°, and 21.7°; or c. the presenceof peaks in the X-ray powder diffraction diagram at the following anglesof refraction 2θ: 5.5°, 7.2°, 11.0°, 11.5°, 14.4°, 16.6°, 18.1°, 21.1°,and 22.0°.
 28. The method according to claim 20, wherein the crystallineform of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride is characterized by: a. the presence ofpeaks in the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 4.0°, 5.0°, 5.9°, 11.7°, 15.3°, 16.9°, 19.3°, 19.7°, and20.7°; or b. the presence of peaks in the X-ray powder diffractiondiagram at the following angles of refraction 2θ: 5.2°, 6.8°, 8.0°,10.3°, 10.8°, 12.7°, 15.4°, 16.2°, 20.3°, and 21.7°; or c. the presenceof peaks in the X-ray powder diffraction diagram at the following anglesof refraction 2θ: 5.5°, 7.2°, 11.0°, 11.5°, 14.4°, 16.6°, 18.1°, 21.1°,and 22.0°.
 29. The method according to claim 21, wherein the crystallineform of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride is characterized by: a. the presence ofpeaks in the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 4.0°, 5.0°, 5.9°, 11.7°, 15.3°, 16.9°, 19.3°, 19.7°, and20.7°; or b. the presence of peaks in the X-ray powder diffractiondiagram at the following angles of refraction 2θ: 5.2°, 6.8°, 8.0°,10.3°, 10.8°, 12.7°, 15.4°, 16.2°, 20.3°, and 21.7°; or c. the presenceof peaks in the X-ray powder diffraction diagram at the following anglesof refraction 2θ: 5.5°, 7.2°, 11.0°, 11.5°, 14.4°, 16.6°, 18.1°, 21.1°,and 22.0°.
 30. The method according to claim 18, wherein the crystallineform of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride is characterized by the presence of peaksin the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 4.0°, 5.0°, 11.7°, 15.3°, and 19.3°.
 31. The methodaccording to claim 19, wherein the crystalline form of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride is characterized by the presence of peaksin the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 4.0°, 5.0°, 11.7°, 15.3°, and 19.3°.
 32. The methodaccording to claim 20, wherein the crystalline form of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride is characterized by the presence of peaksin the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 4.0°, 5.0°, 11.7°, 15.3°, and 19.3°.
 33. The methodaccording to claim 21, wherein the crystalline form of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride is characterized by the presence of peaksin the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 4.0°, 5.0°, 11.7°, 15.3°, and 19.3°.
 34. The methodaccording to claim 18, wherein the crystalline form of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride is characterized by the presence of peaksin the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 5.2°, 6.8°, 10.3°, 10.8°, and 15.4°.
 35. The methodaccording to claim 19, wherein the crystalline form of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride is characterized by the presence of peaksin the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 5.2°, 6.8°, 10.3°, 10.8°, and 15.4°.
 36. The methodaccording to claim 20, wherein the crystalline form of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride is characterized by the presence of peaksin the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 5.2°, 6.8°, 10.3°, 10.8°, and 15.4°.
 37. The methodaccording to claim 21, wherein the crystalline form of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride is characterized by the presence of peaksin the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 5.2°, 6.8°, 10.3°, 10.8°, and 15.4°.
 38. The methodaccording to claim 18, wherein the crystalline form of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride is characterized by the presence of peaksin the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 4.0°, 5.0°, 5.9°, 11.7°, 15.3°, 16.9°, 19.3°, 19.7°, and20.7°.
 39. The method according to claim 19, wherein the crystallineform of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride is characterized by the presence of peaksin the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 4.0°, 5.0°, 5.9°, 11.7°, 15.3°, 16.9°, 19.3°, 19.7°, and20.7°.
 40. The method according to claim 20, wherein the crystallineform of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride is characterized by the presence of peaksin the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 4.0°, 5.0°, 5.9°, 11.7°, 15.3°, 16.9°, 19.3°, 19.7°, and20.7°.
 41. The method according to claim 21, wherein the crystallineform of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride is characterized by the presence of peaksin the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 4.0°, 5.0°, 5.9°, 11.7°, 15.3°, 16.9°, 19.3°, 19.7°, and20.7°.
 42. The method according to claim 18, wherein the crystallineform of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride is characterized by the presence of peaksin the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 5.2°, 6.8°, 8.0°, 10.3°, 10.8°, 12.7°, 15.4°, 16.2°,20.3°, and 21.7°.
 43. The method according to claim 19, wherein thecrystalline form of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride is characterized by the presence of peaksin the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 5.2°, 6.8°, 8.0°, 10.3°, 10.8°, 12.7°, 15.4°, 16.2°,20.3°, and 21.7°.
 44. The method according to claim 20, wherein thecrystalline form of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride is characterized by the presence of peaksin the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 5.2°, 6.8°, 8.0°, 10.3°, 10.8°, 12.7°, 15.4°, 16.2°,20.3°, and 21.7°.
 45. The method according to claim 21, wherein thecrystalline form of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride is characterized by the presence of peaksin the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 5.2°, 6.8°, 8.0°, 10.3°, 10.8°, 12.7°, 15.4°, 16.2°,20.3°, and 21.7°.
 46. A method for manufacturing a pharmaceuticalcomposition comprising as active ingredient4-((R)-2-{[6((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester, or a pharmaceutically acceptable salt thereof, and atleast one pharmaceutically acceptable carrier material, wherein themanufacturing of the pharmaceutical composition comprises the step ofadmixing a crystalline form of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride with the at least one pharmaceuticallyacceptable carrier material; and wherein the crystalline form of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride is characterized by: a. the presence ofpeaks in the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 4.0°, 5.0°, and 15.3°; or b. the presence of peaks in theX-ray powder diffraction diagram at the following angles of refraction2θ: 5.2°, 6.8°, and 10.3°; or c. the presence of peaks in the X-raypowder diffraction diagram at the following angles of refraction 2θ:5.5°, 11.0°, and 16.6°.
 47. The method according to claim 46, whereinthe crystalline form of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride is characterized by: a. the presence ofpeaks in the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 4.0°, 5.0°, 11.7°, 15.3°, and 19.3°; or b. the presenceof peaks in the X-ray powder diffraction diagram at the following anglesof refraction 2θ: 5.2°, 6.8°, 10.3°, 10.8°, and 15.4°; or c. thepresence of peaks in the X-ray powder diffraction diagram at thefollowing angles of refraction 2θ: 5.5°, 7.2°, 11.0°, 11.5°, and 16.6°.48. The method according to claim 46, wherein the crystalline form of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride is characterized by: a. the presence ofpeaks in the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 4.0°, 5.0°, 5.9°, 11.7°, 15.3°, 16.9°, 19.3°, 19.7°, and20.7°; or b. the presence of peaks in the X-ray powder diffractiondiagram at the following angles of refraction 2θ: 5.2°, 6.8°, 8.0°,10.3°, 10.8°, 12.7°, 15.4°, 16.2°, 20.3°, and 21.7°; or c. the presenceof peaks in the X-ray powder diffraction diagram at the following anglesof refraction 2θ: 5.5°, 7.2°, 11.0°, 11.5°, 14.4°, 16.6°, 18.1°, 21.1°,and 22.0°.
 49. The method according to claim 46, wherein the crystallineform of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride is characterized by the presence of peaksin the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 4.0°, 5.0°, and 15.3°.
 50. The method according to claim46, wherein the crystalline form of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride is characterized by the presence of peaksin the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 5.2°, 6.8°, and 10.3°.
 51. The method according to claim46, wherein the crystalline form of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride is characterized by the presence of peaksin the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 4.0°, 5.0°, 11.7°, 15.3°, and 19.3°.
 52. The methodaccording to claim 46, wherein the crystalline form of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride is characterized by the presence of peaksin the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 5.2°, 6.8°, 10.3°, 10.8°, and 15.4°.
 53. The methodaccording to claim 46, wherein the crystalline form of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride is characterized by the presence of peaksin the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 4.0°, 5.0°, 5.9°, 11.7°, 15.3°, 16.9°, 19.3°, 19.7°, and20.7°.
 54. The method according to claim 46, wherein the crystallineform of4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylicacid butyl ester hydrochloride is characterized by the presence of peaksin the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 5.2°, 6.8°, 8.0°, 10.3°, 10.8°, 12.7°, 15.4°, 16.2°,20.3°, and 21.7°.